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Calpain-Cleavage of α-Synuclein: Connecting Proteolytic Processing to Disease-Linked Aggregation
The American Journal of Pathology
  • Brian M. Dufty, Boise State University
  • Lisa R. Warner, Boise State University
  • Kristen M. Leenhouts, Boise State University
  • Julia T. Oxford, Boise State University
  • Troy T. Rohn, Boise State University
Document Type
Article
Publication Date
5-1-2007
Disciplines
Abstract

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are both characterized pathologically by the presence of neuronal inclusions termed Lewy bodies (LBs). A common feature found in LBs are aggregates of α-synuclein (α-Syn), and although it is now recognized that α-Syn is the major building block for these toxic filaments, the mechanism of how this occurs remains unknown. In the present study, we demonstrate that proteolytic processing of α-Syn by the protease calpain I leads to the formation of aggregated high-molecular weight species and adoption of a β-sheet structure. To determine whether calpain-cleavage of α-Syn occurs in PD and DLB, we designed site-directed calpain-cleavage antibodies to α-Syn and tested their utility in several animal model systems. Detection of calpain-cleaved α-Syn was evident in mouse models of cerebral ischemia and PD and in a Drosophila model of PD. In the human PD and DLB brain, calpain-cleaved α-Syn antibodies immunolabeled LBs and neurites in the substantia nigra. Moreover, calpain-cleaved α-Syn fragments identified within LBs colocalized with activated calpain in neurons of the PD and DLB brains. These findings suggest that calpain I may participate in the disease-linked aggregation of α-Syn in various α-synucleinopathies.

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Citation Information
Brian M. Dufty, Lisa R. Warner, Kristen M. Leenhouts, Julia T. Oxford, et al.. "Calpain-Cleavage of α-Synuclein: Connecting Proteolytic Processing to Disease-Linked Aggregation" The American Journal of Pathology (2007)
Available at: http://works.bepress.com/lisa-warner/19/